(A) Biomarkers of Risk of PD. We are conducting a multi-year follow-up study of people with statistical risk factors for PD (family history, olfactory dysfunction, REM behavior disorder, orthostatic hypotension), testing whether evidence of loss of putamen dopaminergic or cardiac noradrenergic innervation indicates the pathogenetic process leading to symptomatic PD. To advertise the study and register and screen candidate subjects we are using a Google Ad and protocol-specific website. So far this effort has been highly successful (more than 27,500 visitors, almost 1400 registrants). (B) Biomarker Patterns in Chronic Autonomic Failure Syndromes. We found that in PD, anosmia (loss of sense of smell) is related to baroreflex failure, cardiac and extra-cardiac noradrenergic denervation, and orthostatic hypotension, independently of striatal dopaminergic denervation. Indices of olfactory and autonomic dysfunction hold promise as biomarkers of pre-symptomatic PD. We also found that anosmia and noradrenergic denervation occur commonly in pure autonomic failure (a rare, important Lewy body disease that features orthostatic hypotension but not parkinsonism) but not in multiple system atrophy, indicating a specific association of both anosmia and sympathetic denervation with Lewy body disorders. We have submitted a new protocol, entitled, Prosthetic Baroreceptor System for Orthostatic Hypotension, as part of the Autonomic Rare Disorders Clinical Research Consortium. The purpose is to determine whether intravenous norepinephrine infusion prevents orthostatic hypotension. Under Protocol 03-N-0004, Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure, we are following patients with pure autonomic failure, to see if they develop dementia or parkinsonism. (C) Collaborations. In a collaborative study with J. Zhang (Univ. of Washington) we supplied CSF neurochemical data and samples from patients with PD, pure autonomic failure, or multiple system atrophy, to correlate clinical and laboratory findings with proteomics results. With Dr. Stephen Kaler (NICHD) we introduced a perfectly sensitive and specific neurochemical assay method for diagnosing Menkes disease. With Dr. Gabor Ilei (NIDCR) we are continuing a collaborative study of autonomic function in Sjogrens syndrome. We are proposing that in collaboration with Y-S Ding (Yale) intramural NIH develop 11C-methoxyreboxetine as a literature compound to visualize central and peripheral sites of noradrenergic innervation. Under a recently approved amendment to NIH Clinical Protocol 03-N-0004, with Christopher Gibbons and Roy Freeman (Harvard) we are planning to study skin biopsy tissues from patients with PD and related disorders. We also plan on sending DNA samples to 23andMe for comparing and contrasting chronic autonomic failure syndromes in terms of frequencies of single nucleotide polymorphisms for catecholamine-related genes. (D) Education &Mentorship. Dr. Goldstein is hosting a year-long sabbatical by Dr. Mee Yeong Park, who is learning autonomic function testing in patients with neurodegenerative disorders and plans to introduce this testing in Korea. Dr. Goldstein supervised a clinical elective by Faisal Rahman (medical student, Univ. of Oxford), and a paper describing Mr. Rahmans research results has been accepted for oral presentation at the upcoming American Autonomic Society meeting. Dr. Goldstein sits on the Examination Committee in autonomic disorders for the United Council of Neurological Subspecialties. With Dr. Cheryl Lohman (Special Volunteer), Dr. Goldstein updated his widely acclaimed handbook for patients with dysautonomias. Dr. Goldstein served on the faculty of the first autonomic nervous system school of the European Federation of Autonomic Societies (Lisbon, July, 2010). He is on the faculty for the upcoming Second World Parkinson Congress (Glasgow, September, 2010), a course on autonomic disorders for primary care physicians at the 21st International Symposium on the Autonomic Nervous System (Marco Island, FL, November, 2010), and the 7th International Congress on Mental Dysfunctions &Other Non-Motor Features in Parkinson's Disease &Related Disorders (Barcelona, December, 2010).